[Hyperammonemia and metabolic-associated fatty liver disease: a complex relationship]

Non-alcoholic or metabolic-associated fatty liver disease (NAFLD/MAFLD) is a non-infectious pandemic of the 21st century, affecting about a third of the adult population worldwide. According to epidemiological studies in the Russian Federation, the prevalence of NAFLD based on the Fatty Liver Index (FLI) is 39.2%. With MAFLD, the activity of ornithine (urea) cycle enzymes may decrease, potentially leading to hyperammonigistia (excessive accumulation of ammonia in tissues) and hyperammonemia. Both conditions have multiple negative effects on different cell and tissue types. The aim of the research was to evaluate the role of ammonia as a potential pathogenic factor in the progression of MAFLD and the development of comorbidity.

The analysis was based on publications sourced from Russian and international databases (eLibrary, PubMed, Google Scholar), using the following keywords: «non-alcoholic fatty liver disease», «metabolically associated fatty liver disease», «ammonia», «hyperammonemia», «urea cycle», «ornithine cycle». All studies related to NAFLD/MAFLD and hyperammonemia, which may contribute to disease progression and multi-organ injury, were included in the review.

There is still limited understanding of the exact mechanisms underlying comorbid pathology in MAFLD and its transition from mild steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. It is the accumulation of fat in the liver that can lead to a decrease in the function of urea cycle enzymes and the development of hyperammonemia. When ammonia level increases, complex biochemical processes in the liver are initiated (apoptosis, inflammation, epigenetic modifications, increased expression of the p53 protein and accelerated cellular aging, etc.), which can induce the transition from mild steatosis to steatohepatitis and further fibrosis and cirrhosis. Hyperammonemia may be an unspecified pathogenic factor contributing to multi-organ disorder and disease progression in MAFLD.

In MAFLD, the activity of urea cycle enzymes may decrease due to epigenetic DNA alterations and accelerated hepatocyte aging (increased p53 expression as an indicator of cellular aging), resulting in hyperammonemia. Hyperammonigistia and hyperammonemia may have negative effects on multiple cell and tissue types (e.g., liver, brain, muscles, cardiovascular and immune systems), contributing to comorbid pathology and a wide range of adverse outcomes. Measuring ammonia levels in patients with MAFLD, especially at advanced stages, and applying measures to reduce them may represent a promising direction in disease management to prevent progression and the development of comorbidity. The mechanisms underlying multi-organ injury in MAFLD, its transition from mild steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma, as well as the role of elevated ammonia, require further investigation.